The vanilloid receptor (VR1) is a member of the transient receptor potential (TRP) superfamily. Members of this family are non-voltage activated cation channel proteins that play critical roles in processes ranging from sensory physiology to vasorelaxation and male fertility. They share structural similarities such as six transmembrane segments and an oligmeric structure (Montell, C. et al., Cell, 108, p 595, 2002). The vanilloid or capsaicin receptor (VR1 or TRPV1) has been cloned from dorsal root ganglia (DRG) of the rat, the human, the chicken, the guinea pig, and the rabbit (Szallasi, A. et al., Pharmacol. Rev., 51, p 159, 1999; Caterina, M. J. et al., Nature, 389, p 816, 1997; Hayes, P. et al., Pain, 88, p 205, 2000; Jordt et al., Cell, 108, p 421, 2002; Savidge, J. et al., Neuropharmacology, 43, p 450, 2002; Gavva, N. R. et al., J. Biol. Chem., in press, 2004). Vanilloid receptor homologues have also been cloned but are not believed to be sensitive to vanilloids (Gunthorpe, M. J. et al, Trends in Pharmacol. Sci., 23, p 183, 2002). VR1, which is expressed predominantly on thin, unmyelinated sensory nerve fibers (C-fibers) and small A fibers in the dorsal root, trigeminal, and nodose ganglia, is a molecular integrator of nociceptive stimuli. VR1 is activated by protons, heat, natural exogenous ligands such as capsaicin (CAP) or resiniferatoxin (RTX), and endogenous substances such as anandamide and the lipoxygenase product 12-HPETE (Tominaga M. et al., Neuron, 21, p 531; 1998; Caterina, M. J. et al., Nature, 389, p 816, 1997; Walpole C. S. J. et al., Capsaicin in the Study of Pain, Academic Press, San Diego, Calif., p 63, 1993; Appendino, G. et al., Life Sci., 60, p 681, 1997; Zygmunt, P. M. et al., Nature, 400, p 452, 1991; Hwang S. W. et al., Proc. Natl. Acad. Sci. U.S.A., 97, p 6155, 2000). Since VR1 functions as a non-selective cation channel with high Ca2+ permeability, its activation by these agents leads to an increase in intracellular Ca2+ that results in excitation of primary sensory neurons and ultimately the central perception of pain. Chronic stimulation of VR1 leads to desensitization/defunctionalization of the neurons, probably reflecting multiple mechanisms.
The involvement of VR1 in both pathological and physiological conditions suggests that the blocking of this receptor, by desensitization or by antagonism, would have considerable therapeutic utility. Among its therapeutic targets, pain is of particular interest. The validation of VR1 as a molecular target for the treatment of chronic pain was confirmed using transgenic mice lacking functional VR1 receptors. These mice exhibited impairment in the perception of thermal and inflammatory pain (Caterina, M. J. et al., Science, 288, p 306, 2000).
The therapeutical advantage of VR1 antagonism over desensitization subsequent to agonism is that it avoids the initial excitatory effect preceding the desensitization. The initial acute pain associated with capsaicin treatment has proven to be the limiting toxicity. After the discovery of capsazepine as the first VR1 antagonist (Walpole, C. S. J et al., J. Med. Chem., 37, p 1942, 1994), a number of antagonists have been reported both with structures related and unrelated to agonists (Walpole, C. S. J. et al, J. Med. Chem., 37, p 1942, 1994). Among them, 5-Iodo-RTX, SC0030, halogenated capsaicin analogues, BCTC, SB-366791, 7-hydroxynaphthalen-1-yl urea, and IBTU were characterized in detail as potent VR1 competitive antagonists (Wahl, P. et al., Mol. Pharmacol., 59, p 9, 2001; Seabrook, G. R. et al., J. Pharmacol. Exp. Ther. 303, p 1052, 2002; Wang, Y. et al., Mol. Pharmacol., 62, p 947, 2002; Suh, Y-G. et al., Bioorg. Med. Chem. Lett., 13, p 4389, 2003; Appendino, G. et al., Br. J. Pharmacol., 139, p 1417, 2003; Valenzano, K. J. et al., J. Pharmacol. Exp. Ther., 306, p 377, 2003; Pomonis, J. D. et al., J. Pharmacol. Exp. Ther., 306, p 387, 2003; Sun, Q. et al., Bioorg. Med. Chem. Lett., 13, p 3611, 2003; Gunthorpe, M. J. et al., Neuropharm., 46, p 133, 2004; McDonnell, M. E. et al., Bioorg. Med. Chem. Lett., 14, p 531, 2004; Toth, A. et al., Mol. Pharm., 65, p 282, 2004).
We have previously reported that isosteric replacement of the phenolic hydroxyl group in potent vanilloid receptor agonists (Lee, J. et al., Chem., 9, p 19, 2001) with the alkylsulfonamido group provided a series of compounds which are effective antagonists to the action of capsaicin on rat VR1 heterologously expressed in Chinese hamster ovary (CHO) cells. As a prototype, N-[2-(3,4-dimethylbenzyl)-3-pivaloyloxypropyl]-N′-[4-(methylsulfonylamino)benzyl]thiourea (1) showed a high binding affinity with a Ki value of 29.3 nM for the inhibition of [3H]RTX binding and potent antagonism with an IC50 value of 67 nM for the inhibition of 45Ca2+ uptake in response to capsaicin, displaying partial agonism (Wang, Y et al., Pharm., 64, p 325, 2003). Compound 2, 3-fluoro analogue, showed very potent antagonism with IC50=7.8 nM and analgesic activity in writhing test (Lee, J et al., Med. Chem., 46, p 3116, 2003).

The present inventors have been extensively endeavored to discover novel analgesic agents based on the above studies and finally completed the present invention by synthesizing novel 4-(methylsulfonylamino)phenyl analogues as vanilloid antagonist showing excellent analgesic activity and the pharmaceutical compositions comprising the same.